Aging is associated with an increase in cardiac hypertrophy, a common prelude to heart failure. The career goal of this application is to provide an additional period of protected, rigorous, training to facilitate the candidate's transition from a fellow to an independent researcher in cardiovascular aging. The applicant's long-term scientific goal is to elucidate endogenous counter-regulatory mechanisms controlling hypertrophy and the progression to failure, as one approach to identifying potential therapeutic targets. Our preliminary data suggest a role for myostatin in the regulation of hypertrophy and aging in the heart. Myostatin is a conserved negative regulator of skeletal muscle that is a potential clinical target in the prevention of muscle wasting diseases such as age-related sarcopenia. The specific aims are to: 1) Examine the role of myostatin in vitro on cardiomyocyte hypertrophy and apoptosis. 2) Define downstream signaling pathways involved. 3) Evaluate the long-term effects of myostatin deletion on the heart at baseline as well as in models of physiological and pathological hypertrophy in vivo. Understanding endogenous mechanisms that limit cardiac hypertrophy may provide novel targets or approaches for managing cardiac hypertropy and failure. The candidate, Michael R. Morissette, is a research fellow in medicine at Massachusetts General Hospital in the Cardiovascular Research Center. The MGH Division of Cardiology has committed institutional support and resources to Dr. Morissette, which will enable him to execute the proposed research plan. During the award period, his sponsor will be Dr. Anthony Rosenzweig, an established cardiovascular researcher and highly experienced, successful mentor. The scientific committee assembled to provide guidance to Dr. Morissette includes experts on cardiovascular aging and clinical heart failure. The career development plan includes formal coursework on the biology of aging, attendance at aging related journal clubs, seminars, and conferences, as well as relevant lab meetings held by any of his committee members. Experiential learning will enhance and expand Dr. Morissette's research skills and knowledge in the area of murine models of cardiac growth (physiologic and pathologic), genetics, and in vivo evaluation. These proposed studies may lead to the elucidation of new therapeutic targets to prevent cardiac hypertrophy and heart failure. Thus the relevance to public health would be a reduction in cardiac morbidity and mortality in the aging population.